2-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenyl → 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(pyridin-2-yl)quinolin-4-amine

HRID 1431349

반응식

HRID 1431349 반응식
CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[CH:42]=[C:43]([NH2:47])[CH:44]=[N:45][CH:46]=2)[CH2:37][CH2:36]1.Cl[C:49]1[C:58]2[C:53](=[CH:54][C:55]([F:60])=[CH:56][C:57]=2[F:59])[N:52]=[C:51]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][N:62]=2)[C:50]=1[CH3:67].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:59][C:57]1[CH:56]=[C:55]([F:60])[CH:54]=[C:53]2[C:58]=1[C:49]([NH:47][C:43]1[CH:44]=[N:45][CH:46]=[C:41]([N:38]3[CH2:39][CH2:40][O:35][CH2:36][CH2:37]3)[CH:42]=1)=[C:50]([CH3:67])[C:51]([C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][N:62]=1)=[N:52]2

참가 물질

8

반응물 4

HCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 23676156Sodium t-butoxideHCID 583477375-Morpholinopyridin-3-amineHCID 596310254-Chloro-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinoline

생성물 1

HCID 509067895,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(pyridin-2-yl)quinolin-4-amine

시약·촉매·용매 3

HCID 9811564Bis(dibenzylideneacetone)palladium촉매HCID 962Water용매HCID 1140Toluene용매

반응 조건

온도
120 °C

실험 절차

To a stirred solution of X-Phos (0.026 g, 0.055 mmol), 5-morpholinopyridin-3-amine (0.074 g, 0.413 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(pyridin-2-yl)-quinoline (0.10 g, 0.344 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.013 g, 0.014 mmol) in toluene (3.44 mL) was added sodium t-butoxide (0.083 g, 0.86 mmol). The reaction mixture was heated to 120° C. and stirred for 45 min. The reaction was then cooled to rt and diluted with water (10 mL). The mixture was extracted with EtOAc (2×10 mL) and DCM (1×10 mL). The organic layers were combined and washed with brine (1×20 mL) and dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography on basic alumina (0 to 50% EtOAc in hexanes) to give the desired product 5,7-difluoro-3-methyl-N-(5-(4-morpholinyl)-3-pyridinyl)-2-(2-pyridinyl)-4-quinolinamine. 1H NMR (400 MHz, CDCl3) δ ppm 8.70 (1H, d, J=4.5 Hz), 7.95 (1H, s), 7.78-7.92 (3H, m), 7.62 (1H, d, J=9.8 Hz), 7.33-7.43 (1H, m), 6.97-7.14 (2H, m), 6.60 (1H, br. s.), 3.79-3.94 (4H, m), 3.12-3.30 (4H, m), 2.16 (3H, s). Mass Spectrum (ESI) m/e=434.2 (M+1).

후처리

  1. temperatureThe reaction was then cooled to rt
  2. extractionThe mixture was extracted with EtOAc (2×10 mL) and DCM (1×10 mL)
  3. washwashed with brine (1×20 mL)
  4. dry with materialdried over magnesium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customThe crude product was purified by column chromatography on basic alumina (0 to 50% EtOAc in hexanes)

출처 및 근거

ORD 기록
ord-c771e5da0aa14fceb60e9460513f00a5
출처 데이터셋
uspto-grants-2015_01
특허 번호
US08940724B2

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